HIV-1 infection and drug abuse are major public health problems in the United States. Drug users are at higher risk for contracting HIV infection and for developing cognitive deficits ranging from minor impairment to frank dementia (HIV-D). A key mechanism of neuronal dysfunction underlying the cognitive impairment in both HIV-D and drug abuse is neuroglial dysfunction. Specific alterations in glutamate metabolism, chemokines and cytokines may contribute to both excitotoxicity and CNS inflammation. The overall goal of this project is to examine whether drugs of abuse (DOA) such as cocaine and heroin, and in combination with HIV-1 infection, synergistically affect levels of glutamate or selected chemokines, resulting in neuronal and glial dysfunction. The central hypothesis is that DOA act synergistically with the products of HIV-1 infection and influence pathways of excitotoxicity, inflammation and neuroglial responses. To address this hypothesis, we will examine the effects of DOA such cocaine and heroin and HIV-1 infection on 1) glutamate uptake and glutamate transporters (GT) and 2) chemokines involved in CNS inflammation such Macrophage Chemoattractant Protein-1 (MCP-1), Stromal derived factor-1 (SDF-1) and fractalkine. First, brain tissues from neurologically characterized patients with HIV-D with and without a history of drug abuse, will be studied to determine the profile of GT and chemokine expression and how these profiles correlate with neuroglial responses. Second, to further assess the role of cocaine and heroin in association with HIV infection, we will use a novel model of human organotypic brain cultures. These cultures will provide the ability to manipulate conditions, assess factors that affect both GT and chemokines, and monitor excitotoxicity. Third, we will use brain tissues from the macaque SIV model, a well studied animal model of HIV infection, to assess the profile of GT and excitotoxicity and determine how these factors affect the profile of neuroinflammatory changes. The results of these studies will facilitate a better understanding of the mechanisms of injury in HIV infection and drug abuse and will provide insight into the design of more effective therapeutics.